Cancer biology and Chemotherapy Flashcards
Summarise the common adverse effect of myelosuppression seen with chemotherapy
Myelosupression occurs in chemo and refers to suppress of bone cells, mainly RBC and WBC
Suppression/destruction of RBC = will cause anaemia and severe fatigue
Suppression/destruction of WBC = weaken the immune system, inc the risk of infections
What chemo drug is known for causing cardiac toxicity?
Doxorubicin
What chemo drug is known for causing renal toxicity?
Cisplatin
What chemo drug is known for causing pulmonary toxicity?
bleomycin
What chemo drug is known for causing neurotoxicity?
Vincristine
Paclitaxel
List the cancer drugs that are DNA synthesis inhibitors
Folate antagonists = methotrexate, pemetrexed
What is the MOA of methotrexate?
Inhibit DNA synthesis due to inhibition of dihydrofolate –> prevent conversion to tetrahydropholate –> prevent IMP formation and thus no DNA synth
Reduce toxicity with folinic acid supplementation
What is the MOA of Pemetrexed?
Inhibit DHFR, tymidylate synthase and glycinamide ribonucleotide formyltransferase (GRAFT) –> prevents DNA synth
Why are DNA synthesis inhibitor chemo drugs delivered intrathecally?
Do not penetrate CNS
What unique cancer can methotrexate be used in?
Trophoblastic tumours
What are some notable ADRs of DNA synthesis inhibitor chemo drugs?
Myelosuppression = think WBC and RBC
Stomatitis and renal tox (methotrexate)
Hepatotox
List the purine analogue chemo drugs
Mecaptopurine = hypoxanthine analogue
Thioguanine = guanine analogue
Used in blood cancers
What is the MOA of purine analogue chemo drugs?
Interfere with DNA synthesis due to inhibition of the biosynthesis of adenine and guanine
Prevent creation of functioning base pairs
What are some notable ADRs with purine anaologues?
thioguanine = produces dose limiting myelosuppression
Mercaptopurine = causes hepatotoxicity
Both drugs contribute to secondary cancer formation
List the halogenated purine analogues used in chemo
FLudarabine
Cladribine
What is the MOA of halogenated purine analogue chemo drugs?
Pretend to be DNA
Incorporated into nascent DNA –> cause DNA chain termination
What unique cancer does cladribine treat?
hairy cell leukaemia
What types of cancers are commonly treated with fludarabine?
blood cancers
List the relevant pyrimidine antagonist drugs used in cancer treatment
Cytarabine (cytosine arabinoside) = composed of cytosine and arabinose sugar
- Iv or Subcut
Fluorouracil = analogue of thymine
- IV = solid cancers
- Topical = non-invasive skin cancers
What is the MOA of cytarabine?
Active metabolites of cytarabine block DNA synthesis
- inhibition of DNA polymerase - Incorporation of drug into nascent DNA --> cause DNA chain termination
What is the MOA of fluorouracil?
Has two active metabolites:
- 5-fluorodeoxyuridine monophosphate (5-FdUMP) --> inhibit thymidylate synthetase --> prevent DNA building block thymidine synthesis - 5-fluorodeoxyuridine triphosphate (5-FdUTP) ---> incorporated into RNA by RNA polymerase --> interfere with RNA function
What genetic material does 5-FdUMP target?
DNA
What genetic material does 5-FdUTP target?
RNA
Describe the rationale behind the combination of fluorouracil and leucovorin
Synergism happens
Allows 5-FdUMP to bind to thymidylate synthase more efficiently –> inc the ability to drop thymidine
What route of administration causes greatest myelosuppression w/ fluorouracil?
More problematic after bolus injection (push-injection)
Mucosal damage is dose limiting with continuous infusion
What is the name of the pyrimidine antagonist which is a cell cycle specific drug?
Gemcitabine –> used as first line in pancreatic cancers
What is the MOA of gemcitabine?
gemcitabine –> converted to gemcitabine diphosphate and triphosphate –> inhibiting DNA synthesis in the S-phase
List the sub-class of DNA alkylating drugs and the relevant drugs within this (sub)-class
Subclass = nitrogen mustards
cyclophosphamide
Ifosfamide
Chlorambucil
Generally explain the MOA of DNA Alkylating drugs
Cross-linking DNA strands by forming covalent bonds between alkyl groups of the drug and guanine bases of DNA —> preventing uncoiling of the DNA
When is nausea worse with cyclophosphamide?
mild with orally
Severe when given IV
What are some notable ADRs of DNA alkylating drugs?
Haemorrhagic cystitis = due to depletion of thiol groups
Cyclophosphamide = dose-limiting myelosuppression
What is the MOA of Platinum compounds used in cancer treatment?
Form intrastrand and interstrand covalent bonds with DNA bases –> cross-link DNA
What can be used to counter the haemorrhagic cystitis seen predominantly with cyclophosphamide?
Administer mesna –> replenish thiol groups and prevent haemorrhagic cystitis
What are some notable ADRs of platinum compounds?
mild myelosuppression
Severe nausea
Nephrotoxicity
Vomiting
What is mitomycin C and what is its MOA?
Antineoplastic abs
MOA = alkylates DNA –> strand breakage –> inhibition of DNA synthesis
What is mitomycin commonly used for
Used along vincristine as salvage therapy for breast cancer
List the relevant DNA intercalating drugs
Anthracycline = Daunorubicin, Doxorubicin
bleomycin
dactinomycin
What are the MOAs of DNA intercalating drugs?
1) intercalation of DNA –> inserts self between DNA strands –> prevents DNA synthesis
2) Inhibits topoisomerase (I, II) –> allows DNA to break during replication –> impaired DNA synthesis
3) Formation of free radicals
*Not absorbed into CNS
What are some notable ADRs of DNA intercalating drugs?
Dose limiting = myelosuppression and cardiac damage
mucosal ulceration, tumour lysis syndrome
IV = severe localised ulceration and necrosis
What is the relationship between PEG liposomal doxorubicin and cardiac toxicity?
Normally = Doxorubicin accumulates in cardiomyocytes –> inc ROS in the mitocondria –> cardiac toxicity –> dec LVEF
PEG liposomal doxorubicin allows for more tissue specific targeting of doxorubicin into cancerous tissues –> more drug will enter cancer cells –> less drug entering healthy cells –> dec in cardiotoxic effects –> lesser impact on LVEF
What is the MOA of bleomycin?
Causes DNA intercalation during the G2 phase of cell replication
Also causes iron-catalysed free radical formation and DNA strand breakage
What are some notable ADRs of bleomycin?
Pulmonary = interstitial fibrosis, hypoxia, death
Mucocutaneous reactions = lack of aminohydralase in skin –> unable to breakdown drug –> drug accumulates in skin (mild stomatitis, skin hyperpigmentation, erythema
List the relevant mitotic inhibitor chemo drugs
Vinca alkaloids = vincristine, vinblastine
IV only, neither enter CNS
Taxanes = paclitaxel and docetaxel
What is the MOA of the Vinca Alkaloids?
Inhibit the assembly of microtubules –> prevent cell division and tumour growth
What are some notable ADRs of vinca alkaloids?
Vincristine = dose-limiting neurotox –> peripheral neuropathy (suppression of deep tendon reflexes, parethesias
- hoarseness in voice, facial palsies, jaw pain
Vinblastine = myelosuppression (dose-limiting) –> little neurotoxicity
What is the MOA of taxanes?
Block microtubule disassembly –> prevent replication/synthesis of new cells
What types of cancers do paclitaxel and docetaxel treat?
Docetaxel = castrate resistance prostate cancer (hormone independent cancer)
Paclitxel =metastatic ovarian and breast cancer
What are some notable ADRs of taxanes?
dose-limiting myelosuppression
Hypersensitivity reactions –> solubility issues
What is the function of topoisomerase I and II?
Topoisomerase I = breaks and reseals single stranded DNA
Topoisomerase II = breaks and reseals in double-stranded DNA
Generally, what do topoisomerase inhibitors do?
Cause permanent strand breaks by inhibiting the resealing of nicked strands of DNA
List the relevant topoisomerase inhibitors and its MOA
Podophyllotoxins (etoposide) = inhibit topoisomerase II
Camptothecin = inhibit topoisomerase I
MOA = inhibition of both topoisomerase -> causing DNA/RNA damage –> prevent further replication –> DNA and cell synthesis
What class of drugs do topoisomerase inhibitors have a synergistic relationship with?
platinum compounds
List the relevant topoisomerase inhibitors
Camptothecin analogues = irinotecan (biliary excretion) and topotecan (renal excretion)
Podphyllotoxins = etoposide
How is irinotecan metabolised?
Rapidly metabolised to active metabolite called SN-38 –> greater anti-tumour activity
SN-38 excreted primarily by bile
What is irinotecan commonly used to treat?
colorectal cancer that has recurred or progressed following fluorouracil therapy
What are some notable ADRs of camptothecin analogues?
Both topotecan and irinotecan = dose limiting myelosuppression
Irinotecan produces diarrhoea
List the relevant targeted drugs that inhibit protein kinases
Imatinib
Dasatinib
Nilotinib
What is the MOA of protein kinase inhibitor (imatinib) targeted drugs?
Inhibit BCR-ABL tyrosine kinase –> inhibit serine-threonine kinase –> dec malignant transformation and proliferation and inc apoptosis
Which protein kinase inhibitors target EGFR?
Erlotinib
What is the MOA of erlotinib?
Protein kinase inhibitor that inhibits EGFR
Dec cell proliferation, inc apoptosis, dec invasion and metastasis, dec angiogenesis
Causing inc cell destruction, slowing cancer cell proliferation
Cetuximab, panitumumab = have same MOA
What is the MOA of venetoclax?
Inhibit BCL-2 –> promotes apoptosis –> activates caspases –> cancer cell death
What is the MOA of sunitinib?
Inhibits VEGFR –> inhibits angiogenesis
Bevacizumab works the same
What is the MOA of rituximab?
Binds CD20 antigen on non-Hodgkin lymphoma cancer –> reduce/impair early cell cycle initiation
What is the MOA of trastuzumab?
recombinant human mab binds to epidermal growth factor-2 (HER2/neu)[tyrosine kinase] –> inhibit cell proliferation
What is the MOA of Ipilimumab?
Antibody that binds CTLA-4 –> preventing release of T cell inhibitory signalling –> T cell activation
What are some notable ADRs of ipilimumab (yervoy)?
Severe/fatal immune mediated ADR = stop drug indefinitely and commence on high dose corticosteroid therapy
Colitis
Hepatitis
Dermatitis
Neuropathies
What is the MOA of pembrolizumab? ADRs?
mab –> bind PD-1 receptor –> block interaction between PD-1 and ligands (PD-L1 and PD-L2)
ADR = colitis, pneumonitis, hepatitis, hypophysitis –> stop tx
What is the MOA of abemaciclib?
CDK 4/6 inhibitor –> interfere w/ cell cycle progression –> halt cancer progression of Her+ve/Her2-ve breast cancer
What is the MOA and ADR of trodelvy?
Sacituzumab govitecan-hziy
Trop2-directed antibody and topoisomerase inhibitor conjugate
ADR = Neutropenia, diarrhoea, N/V
Inc ADR risk w/ reduced UGT1A1 activity
What is the role of tamoxifen in cancer treatment?
Oestrogen antagonist on breasts –> allow shrinkage of tumour
What is the role of aromatase inhibitors (anastrazole and letrozole) in cancer treatment?
Prevent oestrogen synth –> useful in hormone dependent breast cancer
What is an example of a GnRH agonist? What is the MOA of this group?
Leuprorelin
MOA = inc GnRH stimulation which acts on the pituitary –> inc LH on testes –> inc testosterone release –> excessive hormone production –> negative feedback loop of hypothalamus and pituitary –> eventual dec in tumour size/growth due to dec testosterone
What is an example of a GnRH antagonist? What is the MOA of this group?
Degarelix
MOA = Inhibit GnRH –> inhibits release of LH –> no LH effect on testes —> dec testosterone production –> less testosterone action on testes –> hormone sensitive prostate cancer dec
What is an example of an androgen antagonist? What is the MOA of this group?
Flutamide, bicalutamide
MOA = prevent the action of dihydrotestosterone by competitively binding to the androgen receptor and inhibiting the binding of DHT —> inhibition of cell proliferation/DNA replication due to lack of testosterone
What is the MOA of ketoconazole and abiraterone in prostate cancer?
1) inhibit biosynthesis of testosterone
2) Inhibit androstenedione (has role in synth of oestrogen and testosterone) and DHEA DHEAs –> inhibit testosterone release –> reduced cell proliferation
What is an example of 5alpha-reductase inhibitor? What is the MOA of this group?
Finasteride, dutasteride
MOA = inhibit the conversion of testosterone to potent dihydrotestosterone –> slows growth of testosterone dependent prostate cancers
What are some ADRs of androgen-deprivation therapy?
Sexual = genital shrinkage, erectile dysfunction, libido loss
Physical = weight gain, gyno, muscle atrophy
Metabolic = osteoporosis, anaemia, HTN, heart disease, diabetes
Emotional/cognitive
Systemic = fatigue
TUmour “flare” = GnRH agonist –> tumour will worsen initally like GnRH agonist –> tumour will shrink/sx improve
Explain the direct action of radiotherapy
Ionised radiation –> DNA damage –> cells apoptose and die
Explain the indirect damage of radiotherapy
Ionised radiation –> inc free radical production –> DNA damage –> inc cytokine production –> cell death
